Decreased expression of striatal signaling genes in a mouse model of Huntington's disease

Abstract

To understand gene expression changes mediated by a polyglutamine repeat expansion in the human huntingtin protein, we used oligonucleotide DNA arrays to profile approximately 6000 striatal mRNAs in the R6/2 mouse, a transgenic Huntington's disease (HD) model. We found diminished levels of mRNAs encoding components of the neurotransmitter, calcium and retinoid signaling pathways at both early and late symptomatic time points (6 and 12 weeks of age). We observed similar changes in gene expression in another HD mouse model (N171-82Q). These results demonstrate that mutant huntingtin directly or indirectly reduces the expression of a distinct set of genes involved in signaling pathways known to be critical to striatal neuron function.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…These mice, and in particular the R6/2 line, have an early onset of symptoms and a fast progression of the disease, showing a life expectancy of approximately 12 to 17 weeks, depending on the colony. The phenotype and neuropathology observed in these mice replicate several features observed in humans, including a progressive motor Luesse et al, 2001;Bolivar et al, 2003Bolivar et al, , 2004 and cognitive impairment Murphy et al, 2000), weight loss, decreased striatal and brain size (Mangiarini et al, 1996), ubiquitinated nuclear and cytoplasmic inclusions of the mutant protein (Davies et al, 1997;Li et al, 1999), altered levels of neurotransmitters (for review see Cha, 2000) and their receptors (Cha et al, 1998), altered gene expression (Luthi-Carter et al, 2000Zucker et al, 2005), diabetes (Hurlbert et al, 1999;Luesse et al, 2001;Andreassen et al, 2002;Björkqvist et al, 2005), which was previously reported in 10-25% of HD patients (Podolsky et al, 1972;Farrer, 1985), as well as several other neuroendocrine changes for review see Petersén and Björkqvist, 2006), and premature death (Mangiarini et al, 1996). Interestingly, both R6/2 (Gil et al, 2004 and R6/1 (Lazic et al, 2004(Lazic et al, , 2006 mice show a specific decrease in hippocampal cell proliferation and neurogenesis, which may account for some of their cognitive deficits (see below).…”

“…Although no major signs of inflammation have been detected in R6 brains, the up-regulation of certain genes involved in inflammation (Luthi-Carter et al, 2000) and the activation of iNOS and caspase-1 (enzymes that are known to be involved in the inflammatory response) (Chen et al, 2000) have been reported to occur in R6/2 mice. Within this context, a recent study evaluated the potential therapeutic benefits of two commonly used anti-inflammatory drugs (acetylsalicylate and rofecoxib, inhibitors of cycloxygenases 1 and 2, respectively) in both N171-82Q and R6/2 transgenic mouse models of HD (Norflus et al, 2004).…”

Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis

“…If mutant htt can alter the activity of p53, one would predict that cells expressing mutant htt might have numerous changes in their transcriptional profile. In fact, a number of transcriptional alterations have been identified by gene expression profile, RT-PCR, and Northern blot in response to mutant htt (Li et al, 1999;Cha, 2000;Luthi-Carter et al, 2000;Luthi-Carter et al, 2002;Sipione et al, 2002;Kotliarova et al, 2005;Zucker et al, 2005).…”

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

“…However, given the ubiquitous expression of Ataxin-7 16 and its role in gene expression regulation through association with the widely expressed SPT3/TAF9/GCN5 acetyltransferase (STAGA) histone acetylation complex, 17 it is likely that many cell types (including those of unaffected tissues) may show some sign of the transcriptional alterations, considered early manifestations of disease. 18 We thus sought to identify gene expression differences between SCA7 patient and control dermal fibroblasts, which might act as markers of disease progression and therapeutic efficacy. We chose six candidate transcripts previously shown to be differentially expressed in SCA7 models of disease and linked to general, rather than neuronal-or retinal-specific, pathways involved in polyQ pathogenesis.…”